Initial results from a first in human dose escalation trial of a novel immune stimulating oncolytic adenovirus, AdAPT-001<sup>TGF-ß Trap</sup>.
Authors: Anthony Paul Conley, Christina Lynn Roland, Brian Gastman, Victoria Meucci Villaflor, Christopher Larson, Tony R. Reid, Scott Caroen, Babak Alizadeh, Bryan Oronsky, Meaghan Stirn, Jeannie Williams, Erica Burbano, Angelique Coyle, Minal A. Barve, Naveed Wagle, Nacer Abrouk, Santosh Kesari
Journal: Journal of Clinical Oncology (2023)

2550 Background: As a class, oncolytic adenoviruses (OAV), modified agents of the common cold, specifically target and lyse tumor cells, and by expression of cytotoxic transgenes activate an immune response. AdAPT-001 is an OAV, which carries a transforming growth factor beta (TGF-ß) trap that neutralizes the immunosuppressive and profibrotic cytokine, TGF-ß. Preclinically, AdAPT-001 TGF-ß Trap eradicates non-T-cell infiltrated tumors. The aim of this Phase 1 study was to assess the safety and tolerability and, secondarily, the efficacy of AdAPT-001 TGF-ß Trap after single intra-tumoral injection (IT) (Phase 1a) and multidose IT injection (Phase 1b) in patients with advanced refractory solid tumors. Methods: This was an open label, single-arm, multicenter dose escalation design trial. AdAPT-001 TGF-ß Trap was administered by intratumoral injection. 9 patients were in a single-dose group, where doses of 2.5 x 10 11 , 5.0 x 10 11 , 1.0 x 10 12 viral particles (VPs), were tested, and 19 patients with a median age of 70, 5 median prior regimens, and a median ECOG score of 1 received AdAPT-001 every 2 weeks at 1.0 x 10 12 VPs until progression. Results: AdAPT-001 TGF-ß Trap was well tolerated with local inflammation, fever, and fatigue as the main side effects. No dose limiting toxicities, no grade 4 toxicities, or treatment-related serious adverse events (SAEs) were seen. Tumor types were sarcoma (n = 8), melanoma (n = 2), head &amp; neck (n = 5), gastric (n = 1), rectal (n = 1), breast (n = 1), fallopian (n = 1). Biological activity (virus replication, local reactions, and tumor shrinkage) was observed. The duration of local reactions and virus replication suggested that dosing every 2 weeks was appropriate. The overall responses to treatment were as follows: 5 patients had durable stable disease for 6 months or more, 1 patient had a partial response, and 2 patients demonstrated pseudoprogression with inflammation of uninjected as well as the injected tumor, 5 patients had stable disease for approximately 2 months and 15 patients had progressive disease. 2 abscopal responses have been seen to date. The data also suggest a dose-response relationship, with higher and more frequent doses associated with better outcomes. Peripheral lymphocyte subset analysis and serum cytokine analysis are ongoing. Conclusions: AdAPT-001 TGF-ß Trap is well tolerated and no dose limiting toxicities were observed with the single or multidosing protocol described. Evidence of an antitumor effect was seen. The recommended Phase 2 dose was 1.0 x 10 12 VPs administered by intratumoral injection once every 2 weeks. Combination of AdAPT-001 TGF-ß Trap with a checkpoint inhibitor is planned. Clinical trial information: NCT04673942 .